We first described several years ago the finding that chemokine (SDF-1) stimulation of lymphocytes induces very rapid (onset less than or equal to 5 sec) ERM dephosphorylation and inactivation. Given the evidence that phosphorylation contributes to ERM activation, it was plausible that dephosphorylation mediated the inactivation. However, membrane phospho-lipid, especially PIP2, is an additional key mediator of ERM activation. We hypothesized that acute reduction of PIP2 could contribute to ERM inactivation. Specifically, we considered the possibility that chemokine: 1) activates phospholipase C (PLC); which 2) mediates reduction of phosphatidylinositol 4,5-bisphosphate (PIP2); which 3) releases ERM from its association with the plasma membrane; and 4) triggers ERM dephosphorylation. This proposed model is supported by multiple findings we have made, including the following. PLC inhibitor blocks these events. Translocation of GFP-tagged moesin into cytosol and ERM dephosphorylation can be induced either by: transfection with active PLC construct; or by acute targeting of phosphoinositide 5-phosphatase to the plasma membrane. PIP2 dependence cannot be replaced by phosphorylation (modeled by T558D mutation) in either of two assays: association with plasma membrane in cells or in vitro association with cytoplasmic tails of proteins like CD44. These results demonstrate a powerful new role of PLCs in rapid cytoskeletal remodeling and an additional key role of PIP2 in ERM biology, namely hydrolysis-mediated ERM inactivation. A manuscript on these studies is currently under review.